The role of
nitric oxide (NO) in vascular function, host tumoricidal activity, and antiinflammatory effects is well documented. A number of
cytokines induce NO from a variety of cell types. We have demonstrated in murine models that
interleukin 1 alpha (IL-1 alpha) induces acute hemorrhagic
necrosis, microvascular injury, and enhanced clonogenic
tumor cell kill. Effects on the vasculature are observed only in
tumor and not in normal tissues. Using methods established previously in our laboratory, murine
tumor-derived and normal endothelial cells were cultured with
IL-1 alpha, IFN-gamma, or
IL-1 alpha/IFN-gamma at various doses with NO production quantitated through the measurement of
nitrite by the Griess reaction. In
tumor-derived endothelial cells, we demonstrated that neither
cytokine alone was capable of inducing
nitrite but that the combination of
IL-1 alpha/IFN-gamma induced dose-dependent
nitrite, with peak levels observed after 4 days incubation. When
tumor-derived, normal yolk sac, mouse brain, or mouse aortic endothelial cells were treated with
IL-1 alpha (100 units/ml)/IFN-gamma (10 units/ml),
tumor-derived endothelial cells produced significantly more
nitrite when compared to the normal endothelial cells.
Nitrite production from
IL-1 alpha/IFN-gamma was sensitive to the
nitric oxide synthase inhibitors, NG-methyl-
L-arginine or
NG-nitro-L-arginine in a dose-dependent manner. In addition,
dexamethasone significantly inhibited
nitrite production from
IL-1 alpha/IFN-gamma-treated,
tumor-derived endothelial cells. These studies suggest that the antitumor activity of
IL-1 alpha may be mediated through the production of NO from
tumor-derived endothelial cells.